We propose to conduct a series of experiments designed to extend our original findings from the first 5 years of this grant concerning the relationship between polydrug abuse and euphoria in men and women. Specific drug combinations planned for study in women include: cocaine and marihuana and marihuana and ethanol. Drug-induced alterations in electroencephalographic (EEG) activity, evoked potentials, physiological responses, behavioral states, and cognitive function will be studied during acute intoxication. Regional changes in brain electrical activity during intoxication will be quantified using topographic mapping techniques to determine if neurophysiologic changes are correlated with drug-induced euphoria. EEG topographic, mapping procedures will also be used to determine the extent to which prior exposure to marihuana affects the acute cocaine response and if such alterations are modified by pretreatment with potential pharmacotherapeutic agents for cocaine abuse. The effects of short-term maintenance on fluoxetine, amantadine and benztropine on cocaine-induced EEG and behavioral responses will be studied. Studies will be conducted using multiple drug combinations and within-subject designs under double-blind conditions. Plasma drug levels will also be measured to determine if drug-induced euphoria is directly correlated with specific plasma drug levels and to determine if the nature of the observed drug interactions is due to alterations in pharmacokinetic profiles. A second major aim of this proposal is to use EEG and ERP topographic mapping procedures to compare the effects of chronic buprenorphine or methadone on men who are dully dependent on opiates and cocaine. We will monitor cognitive performance of these individuals during various stages of their treatment and after discharge into either a buprenorphine or naltrexone outpatient program. Measures will include auditory and visual P300 evoked potentials, and performance on psycholinguistic tasks. A more detailed analysis of P300 activity will be accomplished by acquiring single sweep data to determine whether latency shifts or amplitude reductions occur. We will address the issue of whether buprenorphine or methadone maintenance alters the EEG and behavioral effects of acute i.v. challenges with morphine and cocaine. The results of these studies should provide new information on polydrug abuse and will assess whether the above series of neurophysiological and cognitive tasks can be used to monitor progress and predict treatment outcome. Data obtained from these experiments will enhance our basic understanding of the nature of the interactions between two drugs of abuse and how this relationship alters drug reinforcement. In addition, the issue of vulnerability to drug abuse will be explored by correlating pre-drug control measures of EEG and event-related potentials with the subsequent cocaine-and marihuana-induced responses. Results from the buprenorphine and methadone maintenance experiments will have direct applications in the management and treatment of individuals who are dully dependent on opiates and cocaine.